Synthesis and Antiviral Evaluation of TriPPPro‐AbacavirTP, TriPPPro‐CarbovirTP, and Their 1′,2′‐cis‐Disubstituted Analogues

Abstract

Herein we describe the synthesis of lipophilic triphosphate prodrugs of abacavir, carbovir, and their 1',2'-cis-substituted carbocyclic analogues. The 1',2'-cis-carbocyclic nucleosides were prepared by starting from enantiomerically pure (1R,2S)-2-((benzyloxy)methyl)cyclopent-3-en-1-ol by a microwave-assisted Mitsunobu-type reaction with 2-amino-6-chloropurine. All four nucleoside analogues were prepared from their 2-amino-6-chloropurine precursors. The nucleosides were converted into their corresponding nucleoside triphosphate prodrugs (TriPPPro approach) by application of the H-phosphonate route. The TriPPPro compounds were hydrolyzed in different media, in which the formation of nucleoside triphosphates was proven. While the TriPPPro compounds of abacavir and carbovir showed increased antiviral activity over their parent nucleoside, the TriPPPro compounds of the 1',2'-cis-substituted analogues as well as their parent nucleosides proved to be inactive against HIV.

Prodrugs of Nucleoside Triphosphates as a Sound and Challenging Approach: A Pioneering Work That Opens a New Era in the Direct Intracellular Delivery of Nucleoside Triphosphates

“…Althought he developmento fp rodrugs of NTPs is very challenging and cumbersome, Meier's group has demonstrated that these kinds of prodrugs are not only synthetically feasible, but that they can also enter into the cellsa nd releaset he bioactive metabolites (nucleoside triphosphates). Thus, they reported an ovel prodrug technology for NTPs, the so-called TriPPPro approach, [15][16][17] that delivers, in ah ighly selective fashion, the NTPs by an enzyme-triggered mechanism.T his approach allowso ne to bypassa ll the phosphorylations teps required for the activation of nucleosides to the corresponding bioactive metabolites (NTPs). Using the same principle that was followed in the DiPPro approach( not maskinga ll the chargeso ft he phosphate groups to prevent the instability of the molecules by stabilizing the reactive phosphate anhydride linkages), in these prodrugs the g-phosphate group of the triphosphate nucleoside was esterified (masked) with acyloxybenzylm oieties.…”

Antiviral nucleoside analogs

“…Surprisingly, despite of the many publications on the synthesis of 5'-triphosphate derivatives of nucleoside analogs, we found in the literature in the last decade only a few studies on their antiviral activity 35,36 and the ability to inhibit viral polymerases thus interrupting the synthesis of viral DNA. 37,38 However, Krayevsky's group, known for their work on the synthesis of thymidine (2) derivatives, 39,40 already in 1989 synthesized 5'-phosphite derivative of 3'-azido-3'-deoxythymidine 74 (Scheme 4) called phosphazide, which demonstrated antiHIV activity and low toxicity on MT-4 cell line.…”

Modified nucleoside triphosphates in bacterial research for in vitro and live-cell applications

“…The advantage of this strategy is that only one hydrolysis step is required by the cells to release the active NTP, bypassing the phosphorylation metabolism steps. 185,186 Although the TriPPPro method has only been utilized in viruses, there are promising signs for its future use in bacteria.…”